In the previous grant period, we completed a trial in patients with previously untreated B-CLL for which we administered the combination pentostatin (P), cyclophosphamide (C) and rituximab (R) (PCR). We observed a 91% response rate in a genetically high-risk CLL cohort with many negative residual disease patients, but we continue to refine the relationship between these risk-stratification parameters and clinical outcome in order to more completely evaluate important relationships between biologic risk factors and disease outcome, including progression-free (PFS) and overall (OS) survival times. The PCR regimen proved equally effective and well-tolerated in elderly patients (age > 70) and those with reduced creatinine clearance and/or performance status. This is exceptional given that other CIT regimens often prove intolerable for both elderly and poor performance status patients. Finally, this regimen has proven to have minimal marrow suppression and very low incidence of major infections. Despite these advances, patients in CR or nPR continue to have detectable MRD; some patients have relapsed and a subset of patients only achieved a PR. We believe the PCR regimen offers an excellent platform from which to modulate and improve CIT-based therapy. In an effort to improve on the PCR regimen, we propose adding the anti-VEGF directed antibody (bevacizumab [Avastin]). This monoclonal antibody has a non-overlapping mechanism of action compared to the other drugs in CIT, and exploits an important survival pathway for CLL B cells. VEGF-based signaling appears to nurture CLL B-cells in an autocrine and paracrine fashion to promote the survival of CLL B-cells. This treatment may help normalize the tumor vasculature and make the tissue site experience more efficient drug delivery with potential for treatment enhancement. Indeed, anti-VEGF therapy has been shown to enhance the efficacy of combination chemotherapy in other malignancies. We believe this adds a more targeted approach to the therapeutic regimen and can facilitate not only an improvement in the CR rate, but also help eradicate detectable MRD. In concert with this study we propose to continue to assess the relationship of the novel prognostic factors already in place as well as newer prognostic factors discovered by our team in order to refine the prognostic models used for prediction of disease response. Thus our two aims include: 1) To determine if the known clinical efficacy of the combination of pentostatin/cyclophosphamide with rituximab can be enhanced with the addition of bevacizumab in previously untreated B-CLL. In addition we will continue to study the association of established and novel prognostic parameters for association with clinical outcome in this trial. Finally we will assess the prospective validation of the importance of different degrees of MRD immediately post-therapy as a predictive surrogate marker of extended PFS. 2) Explore the impact of adding an anti-VEGF agent on in vitro and in vivo alterations of angiogenesis in CLL patients and whether they correlate with clinical response to PCR-B therapy. PUBLIC HEALTH RELEVANCE: Chronic Lymphocytic Leukemia is a very common leukemia in this country and is currently incurable. Because at least 70 percent of all patients will require treatment in order to have an enhanced quality of life, avoidance of complications of the disease and increased survival, we are committed to testing combination therapies in CLL. This proposal is testing the ability of a unique combination of drugs and monoclonal antibodies that, we believe, have the potential to induce high levels of clinical responses with minimal toxicity for CLL patients with progressive disease. Because of the power of this combination approach we will assess the feasibility of defining how complete the response level can be by both assessing node and spleen size using imaging studies (i.e., CT scans) and if patients can have low to negative minimal residual disease by sensitive flow cytometry. In addition, we are testing our ability to select out patients with more high risk disease who may need more vigorous therapy as well as to continue to explore unique stage independent prognostic factors that can be used for sensitive and specific prognosis in a given patient who will receive combination therapy for CLL. [unreadable] [unreadable] [unreadable]